Genetic Variant Appears Associated With Poorer Outcomes in Advanced Prostate Cancer

According to findings from a retrospective analysis published inJAMA Oncology,the testosterone-related genetic variant HSD3B1(1245C) is associated with more aggressive disease in patients with metastatic prostate cancer. This is the first clinical trial to validate the relationship between the variant and clinical outcomes, and the results may help physicians determine which patients are more likely to benefit from more aggressive therapy.¹

“These findings lay the groundwork for more personalized and effective treatments for prostate cancer. If men carry this specific testosterone-related genetic abnormality we may be able to individualize their therapy,” Nima Sharifi, MD, senior author of the study and director of the Center for GU Malignancies Research, Lerner Research Institute, Cleveland Clinic, said in a press release.

                                                                                                                                             

In the study, faster progression to treatment resistance was associated with inheritance of theHSD2B1genotype. The genotype also appeared to be associated with shortened survival despite treatment following development of resistance.

The genotype did not appear to influence outcomes in men with high-volume prostate cancer. Study authors were not surprised by these findings, as prior studies have also demonstrated that disease progression and burden are vastly different in the high- and low-volume groups.¹

Updated clinical data and DNA samples were analyzed retrospectively from men with prostate cancer who were enrolled onthe large randomized phase III clinical trial E3805 CHAARTED.In the trial, androgen deprivation therapy was evaluated alone as monotherapy or in combination with docetaxel to determine the impact that volume of disease had on overall survival (OS). For this analysis, patients were defined as having either an adrenal-permissive genotype, which was defined as having at least 1HSD3B1(1245C) allele, or adrenal-restrictive, which included patients with no HSD3B1(1245C) alleles.²

Overall, 537 patients from the trial were included in the analysis. The adrenal-permissive genotype was present in 270 of 475 white men (56.8%) versus 7 of 52 nonwhite men (13.5%). Investigators focused the analysis on the Caucasian population to isolate the effect of the genotype and eliminate potential confounders.

The mean age of patients was 63 years, and there were no statistically significant characteristics in terms of patient demographics or treatment. ECOG performance status appeared lower in high-volume disease in men with the adrenal-restrictive genotype. More patients in this armhad not developed castration-resistant prostate cancer (CRPC)as of 2 years (70.5%; 95% CI, 60.0%-80.9%) compared with patients in the low-volume disease group with the adrenal-permissive genotype (51.0%; 95% CI, 40.9%-61.2%). The latter arm was associated with a higher risk of developing CRPC after multivariable analysis with a hazard ratio of 1.89 (95% CI, 1.13-3.14;P= .02), and a hazard ratio for death of 1.74 (95% CI, 1.01-3.00; P= .045).

In patients with the adrenal-permissive genotype, the 5-year OS rate was significantly worse at 57.5% (95% CI, 47.4%-67.7%) compared with the adrenal-restrictive genotype of 70.8% (95% CI, 60.3%-81.3%;P = .03). The adrenal permissive arm was also associated with a higher risk of death.

In men with high-volume disease, 5-year OS rates were not significantly different between the adrenal-permissive (37.3%; 95% CI, 29.8%-44.7%) and adrenal-restrictive genotypes (33.1%; 95% CI, 24.7%-41.4%;P= .65). Additionally, men with low-volume disease did not experience benefit from docetaxel therapy compared with men with high-volume disease, regardless of the genotype expression.

Overall, these findings suggest that this genetic variant can be used as a marker of risk for quick progression to treatment resistance in men with low-volume metastatic prostate cancer.¹

“These findings represent a 7-year research story that started at the lab bench and has now reached the patient bedside,” Sharifi said. “As the team has shown here, incorporating genetic testing in prostate cancer as part of routine care has significant potential to improve treatment success and quality and length of life for men with prostate cancer who carry theHSD3B1(1245C) variant. This work is another step in that direction.

References:

1. Cleveland Clinic Researchers Validate link Between Genetic Variant and Poor Outcomes in Men with Advanced Prostate Cancer [news release]. Cleveland, OH: Cleveland Clinic; February 13, 2020. https://cle.clinic/2TwQara. Accessed March 3, 2020.
2. Hearn JWD, Sweeney CJ, Almassi N, et al.HSD3B1Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer [published online February 13, 2020]. Jama Oncol. doi: 10.1001/jamaoncol.2019.6496.